Effects Of Fumaric Acid Esters Research Articles

Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) represents debilitating conditions characterized by degeneration of neuronal cells in specific brain areas, causing disability and death in patients. In the pathophysiology of NDs, oxidative stress, apoptosis and neuroinflammation have a key role, as demonstrated by in vivo and in vitro models. Therefore, the use of molecules with antioxidant and anti-inflammatory activities represents a possible strategy for the treatment of NDs. Many studies demonstrated the beneficial effects of fumaric acid esters (FAEs) to counteract neuroinflammation and oxidative stress. Among these molecules, dimethyl fumarate (DMF) showed a valid therapeutic approach to slow down neurodegeneration and relieve symptoms in patients with NDs. DMF is a methyl ester of fumaric acid and acts as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation. Therefore, this review aims to examine the potential beneficial effects of DMF to counteract oxidative stress and inflammation in patients with NDs.

Persistence and effectiveness of nonbiologic systemic therapies for moderate-to-severe psoriasis in adults: a systematic review.

SummaryBackgroundThe persistence and effectiveness of systemic therapies for moderate‐to‐severe psoriasis in current clinical practice are poorly characterized.ObjectivesTo systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate‐to‐severe psoriasis, exposed to therapy for ≥ 3 months.Methods MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow‐up) or effectiveness [improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA)]. This review was registered with PROSPERO, number CRD42018099771.ResultsOf 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta‐analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow‐up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE‐exposed patients achieved a markedly improved or clear PGA.ConclusionsThe comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real‐world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used.

Long-term real-life safety profile and effectiveness of fumaric acid esters in psoriasis patients: a single-centre, retrospective, observational study.

BackgroundFumaric acid esters (FAEs) are an established systemic treatment for moderate‐to‐severe psoriasis. However, the long‐term clinical safety and effectiveness of continuous FAE monotherapy and combination therapy have not been established.ObjectiveTo examine the long‐term safety and effectiveness of FAEs as monotherapy and in combination with phototherapy or methotrexate in patients with psoriasis treated at a single centre in Germany.MethodsThis monocentric, retrospective observational study, with a follow‐up period of up to 32.5 years, included 859 patients: 626 received FAE monotherapy, 123 received FAEs with concomitant phototherapy and 110 received FAEs with methotrexate.ResultsApproximately half of patients (49.0%) reported adverse events (566 total events), most of which involved the gastrointestinal tract. Serious adverse events were reported in 2.3% of patients, but none were deemed to have a causal relationship with any of the treatment regimens. Adverse events leading to treatment discontinuation were observed in 12.9% of patients. A median duration of 1 year was observed in all three treatment subcohorts (P = 0.70) from initiation of FAE treatment to a 50% response rate, where response was defined as achieving a cumulative static Physician's Global Assessment (PGA) score of ‘light’ and at least a 2‐point reduction in baseline PGA. A 50% response rate for the cumulative Psoriasis Area and Severity Index 75 was achieved in the FAE monotherapy subcohort after a median of 3 years of treatment, in the FAEs + phototherapy subcohort after 6.7 years and in the FAEs + methotrexate subcohort after 8.1 years (P = 0.001).ConclusionAccording to our data, FAEs as monotherapy or in combination with phototherapy or methotrexate are safe and beneficial for long‐term clinical use. However, multicentre, randomized controlled trials are required to establish the clinical value of monotherapy versus combination therapy and the optimal treatment duration.

Fumaric acid esters hypermethylate the miR21 locus and prevent the formation of CCR6+ CD4 T cells in multiple sclerosis.

Abstract Background Dimethylfumarate (DMF) is known to be converted to monomethylfumarate (MMF) by esterases and then metabolized to fumarate and citric acid via the Krebs cycle. In cancer cells, accumulation of fumarate has been shown to inhibit DNA demethylation and that prompted us to investigate whether the immunomodulatory effects of fumaric acid esters (FAEs) in MS patients could also be related to changes of DNA methylation in CD4 T cells. Methods PBMCs were collected for immunophenotyping and CD4 T cell isolation from 54 Naive and 36 DMF treated RRMS patients. In addition, CD4 T cells were also isolated from 7 patients before and after DMF treatment. DNA methylation was analyzed using the Infinium Methylation EPIC BeadChip array. Methylation changes were validated in naïve and memory CD4 T cell cultures in vitro using MassArray EpiTYPER. qPCR was performed to assess the effect of DNA methylation on transcript levels in CD4 T cells. Results DMF treatment was associated with a significant reduction of CCR6+ CD4 T cells and a strong DNA hypermethylation signature in CD4 T cells. The highest levels of DNA methylation in DMF treated patients compared to controls were detected in a DNA region that was spanning the promoter of microRNA-21 (miR21) in both the cross-sectional and longitudinal cohorts. This region was also found to be hypermethylated in naïve CD4 T cells after treatment with MMF in vitro. Naïve CD4 T cells that were treated with MMF also exhibited reduced miR21 and CCR6 transcript levels. Conclusions Our results suggest that by modulating DNA methylation in CD4 T cells, FAEs reduce the expression of miR21 and prevent the production of CCR6+ CD4 T cells, which in recent studies were identified as potentially encephalitogenic in MS patients.

Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium

Objective: Dimethyl fumarate (DMF) is prescribed against relapsing-remitting multiple sclerosis (MS). Here, we investigated the effects of DMF and monomethyl fumarate (MMF), its metabolite in vivo, at the (inflamed) blood–brain barrier (BBB). Methods: Effects of fumaric acid esters were analyzed using primary human brain–derived microvascular endothelial cells (HBMECs) in combination with peripheral blood mononuclear cells (PBMCs) derived from DMF-treated MS patients. Results: MMF-binding to brain endothelium cells leads to activation of nuclear factor (erythroid-derived 2)–related factor 2 (Nrf2)–induced downregulation of vascular cell adhesion molecule 1 (VCAM-1). This might be mediated via the G-protein-coupled receptor (GPCR) hydroxycarboxylic acid receptor 2 (HCA2), a known molecular target of MMF, as we could demonstrate its expression and regulation on HBMECs. DMF treatment in vivo led to a strongly reduced expression of VCAM-1’s ligand very late antigen 4 (VLA-4) by selectively reducing integrin high-expressing memory T cells of MS patients, potentially due to inhibition of their maturation by reduced trans-localization of NFκB. Conclusion: DMF-mediated VCAM-1 downregulation on the endothelial side and reduction in T cells with a migratory phenotype on the lymphocyte side result in a synergistic reduction in T-cell adhesion to activated endothelium and, therefore, to reduced BBB transmigration in the setting of MS.

The effects of fumaric acid esters on inflammatory responses in human microglia

The effects of fumaric acid esters on inflammatory responses in human microglia

Dimethylfumarate induces apoptosis in human mast cells

Mast cells modulate autoimmune diseases such as psoriasis and multiple sclerosis. Fumaric acid esters (FAEs) are widely used for the treatment of psoriasis, and dimethylfumarate (DMF) has recently been approved for multiple sclerosis. In this study, we analysed the cytotoxic effect of FAEs on human mast cells. Specifically, cell death was analysed in the human mast cell line HMC-1 and in primary cord blood-derived mast cells (CBMCs) after incubation with fumaric acid (FA), monomethylfumarate (MMF), DMF and calcium bis(monomethylfumarate) (Ca-MF). Our data show that only DMF potently induces apoptotic cell death in HMC-1 cells and CBMCs. DMF-mediated apoptosis was associated with increased expression of Bax and Bak and activation of caspase-9 and caspase-6. Interestingly, DMF also enhanced the sensitivity of CBMCs towards TRAIL- and dexamethasone-induced apoptosis. These findings demonstrate for the first time that DMF induces apoptosis of human mast cells, primarily via the mitochondrial apoptotic pathway. Our study contributes to the understanding of the beneficial effects of FAEs in autoimmune diseases and provides a rationale for exploiting FAEs for other diseases associated with mast cells.

Effects of fumaric acid esters on blood–brain barrier tight junction proteins

The blood–brain barrier (BBB) is composed of a network of tight junctions (TJ) which interconnect cerebral endothelial cells (EC). Alterations in the TJ proteins are common in inflammatory diseases of the central nervous system (CNS) like multiple sclerosis (MS). Modulation of the BBB could thus represent a therapeutic mechanism. One pathway to modulate BBB integrity could be the induction of nuclear-factor (erythroid derived 2) related factor-2 (Nrf2) mediated oxidative stress responses which are targeted by fumaric acid esters (FAE). Here we analyze effects of FAE on the expression of TJ proteins in the human cerebral endothelial cell line hCMEC/D3 and experimental autoimmune encephalomyelitis (EAE). We show that dimethylfumarate (DMF) and its primary metabolite monomethylfumarate (MMF) induce the expression of the Nrf2/NQO1 pathway in endothelial cells. Neither MMF nor DMF had a consistent modulatory effect on the expression of TJ molecules in hCMEC/D3 cells. Tumor necrosis factor (TNFα)-induced downregulation of TJ proteins was at least partially reversed by treatment with FAE. However, DMF had no effect on claudin-5 expression in EAE, despite its effect on the clinical score and infiltration of immune cells. These data suggest that the modulation of the BBB is not a major mechanism of action of FAE in inflammatory demyelinating diseases of the CNS.

Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte-endothelial cell interactions

Although fumaric acid esters (FAE) have a decade-long firm place in the therapeutic armamentarium for psoriasis, their pleiotropic mode of action is not yet fully understood. While most previous studies have focused on the effects of FAE on leucocytes, we have addressed their activity on macro- and microvascular endothelial cells. As detected both on mRNA and protein levels, dimethylfumarate effected a profound reduction of TNFα-induced expression of E-selectin (CD62E), ICAM-1 (CD54) and VCAM-1 (CD106) on two different endothelial cell populations in a concentration-dependent manner. This reduction of several endothelial adhesion molecules was accompanied by a dramatic diminution of both rolling and firm adhesive interactions between endothelial cells and lymphocytes in a dynamic flow chamber system. Dimethylfumarate, at a concentration of 50 μm, reduced lymphocyte rolling on endothelial cells by 85.9% (P<0.001 compared to untreated controls), and it diminished the number of adherent cells by 88% (P<0.001). In contrast, monomethylfumarate (MMF) influenced neither surface expression of adhesion molecules nor interactions between endothelial cells and lymphocytes. These observations demonstrate that endothelial cells, in addition to the known effects on leucocytes, undergo profound functional changes in response to dimethylfumarate. These changes are accompanied by severely impaired dynamic interactions with lymphocytes, which constitute the critical initial step of leucocyte recruitment to inflamed tissues in psoriasis and other TNF-related inflammatory disorders.

Effects of fumaric acid esters on differentiation of dendritic cells in vitro

OBJECTIVE: To investigate the effect of anti-psoriatic drug fumaric acid esters (FAE) on the differentiation of dendritic cells (DC). METHODS: Dendritic cells were obtained by differentiating human monocytes in vitro. Flow cytometry was used to analyse the effect of FAE on cell surface expression of CD1a, CD14, CD40, CD80, CD86 and HLA-DR by monocyte-derived dendritic cells (MoDC). Mixed lymphocyte reaction (MLR) was made to demonstrate the influence of FAE on T cell stimulatory activity of MoDC. RESULTS: Dimethylfumarate and methylhydrogenfumarate-calcium-salt (0.01 approximate, equals 100 mg/L) inhibited MoDC differentiation as well as reducing the capacity of MoDC to stimulate lymphocytic proliferation in MLR. CONCLUSION: The mode of action of FAE in pso riasis may be mediated by inhibition of DC differentiation.

Fumaric Acid Esters Suppress Peripheral CD4- and CD8-Positive Lymphocytes in Psoriasis

Background: For severe forms of psoriasis vulgaris, the antipsoriatic fumaric acid esters (FAE) therapy has recently gained increasing acceptance and importance. Until today, there is little knowledge about the mode of action of FAE. However, some evidence exists indicating immunosuppressive effects. Objective: The aim of this study was to examine the systemic, particularly the immunological changes in patients suffering from psoriasis treated with FAE over a long period of time, since we expect to see pharmacological effects of FAE at this point. Methods: This study is based on continuously recorded clinical data and laboratory parameters of 10 patients, who were treated over a period of 12 months with FAE. A quantitative analysis of lymphocytes and their subtypes was carried out by means of flowcytometric methods. Results: 3 months after starting treatment with FAE, a clinical effect with a remission index >95% was achieved in all 10 patients examined. This remained constant until the end of this study. Focusing on leukopenia, and particulary on lymphopenia as important parameters, these effects were found in all patients. The lymphocyte subpopulations data demonstrated extensive proportionate reductions. Within the T cell fraction a stronger suppression of CD8⁺ lymphocytes was observed. Conclusion: Our investigations of systemic effects of fumaric acid esters demonstrate the suppressive character of this medication. Effects of cell count reduction in leukocyte and lymphocyte numbers over the entire period of 12 months could be observed. The lymphocytic cell count number is obviously linked to the clinical effect.